Pharmacokinetics Flashcards
Name some facts about buspirone?
- Causes no dependence
- Doesn’t have street value
- Doesn’t cause tolerance
- Can be withdrawn easily
- Has to be dose TDS as has a short half life
Quetiapine has a….
Short half life (7 hours) compared to Olanzapine/Clozapine/Risperidone
Name some drugs which undergo very little hepatic metabolism and therefore detectable in urine?
Gabapentin, Lithium, Amisulpride and Sulpride
Why can Aripiprazole be dosed at OD
As it has a long half life of 72 hours
Pethidine + BLANK can cause a fatal serotonin syndrome?
MAOI - tranylcypromine or phenelzine
Name some receptors that Clozapine has effects on
Anatgonism:
- D1
- D2 –> weak affinity - at clinically effective doses may only occupy 40-50% of striatal D2 receptors. ? reason why low propensity for EPSEs
- D4 –> strong affinity
- Alpha 1 adrenergic receptors
- H1
- 5-HT2a
Agonism:
- M4 –> ? mechanism behind silaorrhoea
If someone is presenting with alcohol withdrawal and has severe liver damage what benzodiazepines may be of choice?
Oxazepam or Lorazepam
- both short acting
- These benzodiazepines (w/ temazepam) do not undergo phase 1 metabolism through cytochrome P450 enzymes and are instead proceed straight to phase 2, are conjugated (glucuronidation) and excreted.
What does a high therapeutic index mean?
A drug is very safe in relation to clinical effectiveness
Methods of calculating indices include:
- Medium lethal dose (LD-50) / medium effective dose (ED-50)
- Minimum toxic dose / minimum effective dose
Drugs OTC will have a higher therapeutic index i.e paracetamol
Outline the hepatic enzyme inducers or inhibitors?
Inducers:
Carbamazepine
Rifampicin
Alcohol (chronic)
Phenytoin
Gresofulvin
Phenobarbitone
Smoking
St Johns Wart
Topiramate
Inhibitors:
SICK ACES COM GAQ
Sodium Valproate
Isoniazid
Cimetidine
Ketokonazole / Fluconazole
Alcohol (acute)
Chlorphenicol
Erythromycin
Sulfamides
Ciprofloxacin
Omeprazole
Metronidazole
Grapefruit juice
Amiodarone
Quinidine
Broadly name some medications that undergo metabolism by the P450 system?
Most anti-depressants / antipsychotics
Benzodiazepines
Warfarin
Zolpidem
Sodium Valproate
Methadone
Thyroxine
Oestrogen
Steroids
Name a reversible MAOI
Moclobemide (rMAO-A inhibitor) - reversible MAOIs are preferable given there is less tendency for the cheese reaction
Which anti-depressants have been associated with a therapeutic window
Imipramine, Desipramine and Nortrptyline (although dubious benefit of the value of them)
Name some psychotropic drugs that can be given in hepatic impairment?
Antipsychotics - Amisulpride and Sulpride - no dosage reduction if renal function is normal. Paliperidone if depot needed
Anti-depressants - Paroxetine, Vortioxetine, Citalopram, Sertraline
Hypnotics - Lorazepam, Oxazepam and Temepezam - these have no active metabollites. Can be used cautiously starting at a low dose as sedatives may trigger hepatic encephalopathy. Zopiclone 3.75mg may be used also.
Why may Zolpidem be a good choice for hypnotic?
Peak level at 1.6hrs, half-life 2.6hrs
No active metabolites
These make it short acting therefore if a patient needs to do an activity in the morning and can’t be sedated
When does a drug which does not require a loading dose reach a steady state?
4-5 half lives
Name the active metabolites of imipramine and amitriptyline
Imipramine - Desipramine
Amitriptyline - Nortryptiline
Both through cytochrome P450 enzymes
Outline the differences between zero order and first order kinetics?
1st order kinetics - the rate of drug elimination (per unit of time) is proportion to the concentration of the drug.
Zero-order kinetics - the rate of drug elimination is not
Outline the differences between zero order and first order kinetics?
1st order kinetics - the rate of drug elimination (per unit of time) is proportion to the concentration of the drug.
Zero-order kinetics - the rate of drug elimination is not proportional to drug concentration - static rate of elimination. Occurs when elimination is saturated at higher doses. Present for alcohol, high dose salicylates, high dose fluoxetine and high dose omeprazole.
What does clearance depend on?
The half-life of a drug
Define clearance
The volume of blood cleared of a particular drug in a unit of time.
It represents the relationship between elimination rate and drug concentration.
Rate of clearance determines the half-life of a drug
What is autoinduction?
Where a drug induces its own metabolism - this occurs for Carbamazepine therefore it takes 2 weeks for it to reach a steady state
Name an anti-depressant that undergoes autoinhibition?
Paroxetine - CYP450 2D6 inhibitor
Increasing the dose by 50% may lead to double plasma concentration
How does Fluoxetine increase the effect of warfarin
Through P450 inhibition - increases warfarin levels, also haloperidol, carbamazepine, phenytoin
How does Clonidine work?
Through agonism of presynaptic alpha-2 adrenergic receptors.
Decreases sympathetic outflow causing vasodilation and less NAA release from presynaptic nerve terminals - lowers arousal and sympathetic tone
Which SSRIs are most specific for serotonin reputake?
Citalopram
Escitalopram
Have less effect on NAA, GABA and H1
How does pharmacokinetics differ in the elderly?
Reduced rate of absorption
- lower Gastric pH
- less mesenteric blood flow
- less gut motility
Reduced distribution but increased levels with longer half lived
- Reduced plasma protein binding m- less albumin
- Lower BMI with proportionally increased body fat
Reduced metabolism:
- Less liver breakdown from reduction in efficiency of enzymes and less liver blood flow
Reduced excretion:
- Less renal clearance
- Drug effects are prolonged, cumulative with higher risk of toxicity
What are the least sedating TCA’s?
Lofepramine and Nortryptyline
- Lofepramine safest in elderly as least likely to cause postural hypotension, lowest propensity for cardiac conduction abnormalities
How is amphetamine intoxication treated?
Urinary acidification - give ammonium chloride every 2-3 hours and the urine is acidified to help clear the amphetamine
Name 3 factors that affect absorption of a drug?
Form of the drug - enteric coating etc.
Blood flow at the site of absorption
Solubility of the drug - particle size, pH, pKa of the drug (half of the drug in ionised form)
Name some factors that reduce the absorption of drugs from the GI tract?
Changes to gastric pH
Food - delays gastric emptying
Intestinal motility changes - diarrhoea
Blood flow integrity
Surface area available
Inhibitors of P-glycoprotein (a transporter that pumps drugs out of intestinal wall into gut) - grapefruit juice is an inhibitor - can increase absorption of benzodiazepines/carbamazepine, calcium channel blockers etc
Dissolution and disintegration of drugs - takes longer for those with enteric coating/wax mixed in - slow release forms take longer to peak therefore less side effects
Gut flora - some have enzymes that aid metabolism of drugs
Name some factors that affect distribution
Haemodynamic factors - cardiac output
Lipid solubility - permeability factors
Plasma protein binding
Blood-brain barrier
Blood-CSF barrier
Name a condition where protein binding reactions may be important?
Renal disease - proteinuria
There may be less albumin or apha-1 acid glycoprotein therefore free fraction could increase
Name the properties a particle needs to have to cross the BBB
- Unionised
- High lipophilic - water coefficient
However those with a low lipid-water coefficient may still be able to cross through carrier transporters (Valproate or L-DOPA) or through cerebral circulation e.g. Lithium Ions
Subfornical organ, area postrema of the medulla and median eminence make up the…
Circumventricular organs - no BBB - useful to detect toxic substances easily so can initiate vomiting etc
What is bioequivalence?
The degree of comparability between two formulations of the same drug
Need to have same bioavailability and rate of absorption
Name the four major metabollic reactions
Oxidation, reduction, hydrolysis and conjugation
What are the two routes of metabolism
Phase 1: oxidation, reduction, hydrolysis - generally done by CYP450 enzymes. Active/inactive metabolite then ready for conjugation
Phase 2: conjugation by adding glucuronic acid. Makes a more polar - water soluble ready for excretion in bile or urine dependent on relative molecular mass. If mass < 300 in urine.
Name two CYP450 enzymes that psychotropics are typically broken down by?
CYP2D6 - can be inhibited by fluoxetine, amitriptyline, clomipramine & neuroleptics -drugs metabolised:
- All TCAs
- fluoxetine, paroxetine
- trazodone, nefazodone
- valproate, all neuroleptics, risperidone
CYP3A4 (in gut wall) - barbiturates and carbamazepine inducer, fluoxetine can inhibit:
- Clomipramine
- Fluvoxamine,
- Mirtazapine,
- Nefazodone,
- Carbamazepine
- most benzodiazepines
How do Fluxoetine and Fluvoxamine affect metabolism of psychotropics?
Inhibitor CYP450 enzymes (2D6 and 2C19) and can increase levels
- Fluvoxamine may increase level of Clozapine 10 fold
How do smoking and caffeine affect the metabolism of some psychotropic drugs?
Influence glucuronidation reaction via CYP1A2 or UGT enzyme
Caffeine inhibits CYP1A2 - increases levels of Clozapine and Olanzapine
Smoking induces CYP1A2 - lowers levels
What drug forms are suitable for renal excretion?
Ionised and non-lipid soluble
What factors affect renal excretion?
- Age
- Blood flow to kidneys
- Renal impairment
- pH in the urine
Name some drugs that undergo almost all renal excretion without any hepatic breakdown
Lithium, Sulpride, Amisulpride, Gabapentin, Acamprosate, Amantadine
What is distribution half-life?
Time taken from initial peak (Cmax) to half i.e. the time that redistribution halves the initial peak
What is elimination half life?
The time taken for elimination to halve the plasma concentration - most relevant for clinicians
indexWhen is a steady state of a drug achieved?
When 4-5 half lives have been administered
Steady state is rate in = rate out
Name some drugs with a narrow therapeutic index range?
Lithium, Carbamazepine, Phenytoin
How does therapeutic window and therapeutic index range differ?
Therapeutic window - only concerns therapeutic range i.e. above does not consider toxicity
Therapeutic index range - considers effect and safety/toxicity
Name some careful prescribing tips for Renal impairment
Benzodiazepines with caution:
- Diazepam metabolite can accumulate
- Half life of Lorazepam increased from 8-25 to 32-72. If impairment consider halving dose
Antipsychotics
- Avoid Lithium/Amisulpride (later all renally excreted)
- Haloperidol ok unless causing SE - monitor for sedation/postural hypotension
- Risperidone metabolite can accumulate
Anti-D:
- Sertraline avoided
- Amitriptilyine and Imipramine - no dose reduction needed
- Dose reductions for Citalopram and Paroxetine
- Fluoxetine and Fluvoxamine ok
How protein bound are TCAs?
Extensively bound - imipramine 80-95%
After 5 half lives how much of a drug is in a steady state?
97%
After 7 half lives 99% of a drug is in a steady state
A patient’s clozapine level + 1mg/L wyd?
Reduce dose +/- prescribe anticonvulsant coverage (not bone marrow due as its an enzyme inducer and can also suppress bone marrow)
A patient’s clozapine level + 1mg/L wyd?
Likely reduce dose +/- prescribe anticonvulsant coverage (not bone marrow due as its an enzyme inducer and can also suppress bone marrow)
> 2mg/L definitely reduce the dose and prescribe an anticonvulsant
Which clozapine complication is dose related?
Seizures - the other are idiosyncratic or allergic in nature
What is the optimum clozapine dose?
0.35-0.6 mg/L
Why may clozapine:norclozapine ratio be helpful?
Can indicate non-compliance
Should be 1.33:1 (or 0.66:1 if norclozapine:clozapine)
If clozapine:norclozapine is < 1 could indicate non-compliance - to be interpreted with caution given genetic factors, incorrect sampling time and the influence of other drugs e.g. fluovaxmine - inhibitor
Name some drugs that may cause Lithium levels to increase due to poor renal excretion?
NSAIDs
Thiazide like diuretics (not loop/K+ sparing)
ACEi
Angiotensin-II-blockers
Note hyponatraemia can also elevate lithium levels through increased reabsorption at renal tubule
Name some drugs which Carbamazepine reduces the concentration of?
Clozapine, risperidone, amitriptyline - through CYP1A2, CYP2C19, CYP3A enzyme induction
Carbamazepine takes 2-3 weeks to reach a steady state
Therapeutic drug window 4-10mg/L
What drugs may increase levels of Carbamazepine
Clarithromycin, Fluconazole and Diltiazem
Why should combination of anti-D fluoxetine/paroxetine + TCA matter?
Fluoxetine/Paroxetine are inhibitors of CYP450 system therefore the dose of TCAs will go up increasing risk of serotonin syndrome
If augmenting Clozapine what plasma concentration should be aimed for?
< 1mg/L
